The present invention relates to compounds that are melanocortin receptor agonists, to the preparation thereof and to the therapeutic use thereof.
Melanocortin receptors (MC-Rs) belong to the superfamily of G protein-coupled seven-transmembrane domaine receptors. Their transduction pathway involves the production of cAMP (Cone, R. D., Recent Prog. Horm. Res., 1996, 51, 287). Five MC—R subtypes have currently been described, MC1-R, MC2-R, MC3-R, MC4-R and MC5-R, and are expressed in various tissues, such as the brain (MC3, 4, 5-R), the exocrine glands (MC5-R), the adrenals (MC2-R) and the skin (MC1-R), as regards the main ones. The natural ligands of MC-Rs are, as regards the agonists, ACTH, and α-, β- and γ-MSH, and as regards the antagonists, agouti protein and agouti-related protein. None of the natural ligands is very selective for one of the subtypes, with the exception of γ-MSH, which have a certain selectivity for MC3-R.
The melanocortin system is involved in many physiological processes, including pigmentation, inflammation, eating behaviour and sexual behaviour (in particular erectile function), energetic balance (regulation of body weight and lipid storage), exocrine functions, neuronal protection and regeneration, immunomodulation, analgesia, etc.
In particular, it has been demonstrated that MC4-R is involved in sexual behaviour (Van der Ploeg, L. H., Proc. Natl. Acad. Sci. USA, 2002, 99, 11381; Martin, W. J., Eur. J. Pharmacol., 2002, 454, 71). It has also been demonstrated, by means of mouse models specifically devoid of certain MC-Rs (knockout mice), that the central MC-Rs (MC3 and 4-R) are involved in eating behaviour, obesity, the metabolism and energetic balance (Huszar, D., Cell, 1997, 88(1), 131; Chen, A. S., Nat. Genet., 2000, 26(1), 97; Butler, A. A., Trends Genet., 2001, 17, pp. 50-54). Thus, MC4-R knockout mice are hyperphagic and obese. In parallel, MC3 and/or 4R antagonists promote food intake, whereas the stimulation of MC4-Rs by an endogenous agonist, such as α-MSH, produces a satiety signal.
These observations imply that the stimulation of central MC3-R and/or MC4-R, reducing food intake and body weight, is a promising approach for treating obesity, which is an aggravating risk for many other pathologies (hypertension, diabetes, etc.). Thus, research studies have made it possible to identify, initially, peptides, pseudopeptides or cyclic peptides capable of interacting with MC-Rs and of thus modulating food intake.
In order to maintain an effective weight loss in the long term and thus to limit comorbidities, a long-term daily treatment must be envisaged. This implies that a medicament, for this therapeutic indication, must be able to be administered simply by the patient. Oral administration must therefore be favoured. Now, peptide compounds are not generally the most suitable for satisfying this need. For this reason, it is important to develop small non-peptide molecules.
In this perspective, international PCT applications published under the numbers WO 02/059095, WO 02/059108, WO 03/009850 and WO 03/061660 describe piperazine-type derivatives. Other applications describe piperidine-type derivatives, such as WO 03/092690 and WO 03/093234. Applications WO 99/64002 and WO 01/70337 describe spiropiperidine-type derivatives. Application WO 01/91752 describes derivatives containing a piperidine unit fused with a pyrazolyl ring. Application WO 02/059107 describes piperidine-type and piperazine-type derivatives substituted with a bicyclic structure. Applications WO 02/059117, WO 02/068388 and WO 03/009847 describe piperidine-type and/or piperazine-type derivatives substituted with a phenyl ring. As regards application WO 03/094918, it describes piperazine-type derivatives substituted with a phenyl or pyridinyl ring. Mention may also be made of applications WO 00/74679, WO 01/70708, WO 02/15909, WO 02/079146, WO 03/007949 and WO 04/024720, which describe substituted piperidine-type derivatives, or else application WO 04/037797; the compounds described in those patent applications always contain an amide function, that mimics the peptide structures previously known.
Faced with the constant need to improve existing therapies for the pathologies mentioned above, the inventors gave themselves the aim of providing novel compounds that are melanocortin receptor agonists.